SUMMARY Complex interactions between the nervous and immune systems, as main sensors of the body, play a significant role in homeostasis of the cornea. Neurotrophic molecules are vital for maintenance of nerves in peripheral tissues, however, despite our understanding on the impact and diversity of neurotropic molecules in the cornea, their sources and the mechanism through which their production is regulated remains elusive. Our preliminary results suggest that certain populations of leukocytes, in particular plasmacytoid dendritic cells (pDCs), can serve as essential source of neurotrophic molecules. Thus, in this application, we propose evaluating the contribution of each subpopulation of immune cells in providing corneal nerves with the neurotrophic molecules and the signaling mechanism through which activation of immune cells through toll like receptors (TLRs) may alter their neurotrophic properties. Further, we aim to assess if local adoptive transfer of subpopulation of immune cells may enhance nerve regeneration following nerve damage in the cornea. We also aim to determine if resident corneal immune cells regulate function of corneal nerves by depleting each subpopulation of the resident corneal leukocyte and assessing electrical conduction of corneal nerves via electrophysiological studies as well as measuring the response to painful stimuli in the pain centers in central nervous system. Next, we propose to study how corneal nerves (both sensory and autonomic) may regulate several steps in immune reaction, from up-regulation of adhesion molecules and increasing the permeability of limbal vessels to recruitment of immune cells to the cornea and their intra-corneal locomotion. We suggest studying how corneal nerves shape multiple functions of immune cells, including capacity of antigen uptake and presentation to effector cells, profile of secretory cytokines, and angiogenic molecules. The application proposes a paradigm shift on how corneal nerves may mediate immunity, and would potentially introduce new immunomodulatory therapeutic strategies and targets for ocular as well as systemic inflammatory, autoimmune, alloimmune and infectious diseases.